TACI-CRD2 protein domain

Function

TACI functions as a negative regulator of BAFF function given that loss of TACI expression results in the overproduction of B lymphocytes, a type of white blood cell that guards against infection. Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities.

Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a cytotoxin which is derived from a form of white blood cell called monocytes. It is thought to cause tumour regression, septic shock and cachexia. The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers. Both the mature protein and a partially processed form of the hormone are secreted after cleavage of the propeptide.

There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors. TACI is a member of the tumor necrosis factor receptor superfamily and has an important role as regulator of B cell function. TACI binds two ligands, APRIL and BAFF, which it binds to with high affinity and contains two cysteine-rich domains (CRDs) in its extracellular region.

Formation

TACI-CRD1 forms TACI-CRD2 by removing the N-terminal cysteine rich domain by alternative splicing. This shorter form is capable of ligand-induced cell signaling and that the second CRD alone (TACI-CRD2) contains full affinity for both ligands.

Ligands

The ligands are type II transmembrane protein cytokines that have various effects on immune cells, including acting as a:

• costimulatory molecules,
• apoptotic agents,
• growth factors

APRIL (also known as TNSF13A, TALL-2, and TRDL-1) is a TNF ligand that is overexpressed by some tumours.

References

References

1. (February 2005). "Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding". J. Biol. Chem..
2. (February 1993). "A 3-D model for the CD40 ligand predicts that it is a compact trimer similar to the tumor necrosis factors". Int. Immunol..
3. (July 1992). "Emerging cytokine family". Nature.
4. Bazan JF. (September 1993). "Emerging families of cytokines and receptors". Curr. Biol..
5. (June 1985). "Molecular cloning of mouse tumour necrosis factor cDNA and its eukaryotic expression". Nucleic Acids Res..
6. (April 1988). "A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF". Cell.
7. (December 1990). "Characterization of high molecular weight glycosylated forms of murine tumor necrosis factor". Biochem. Biophys. Res. Commun..
8. (September 1989). "Alternative cleavage of the cachectin/tumor necrosis factor propeptide results in a larger, inactive form of secreted protein". J. Biol. Chem..